S100A9 upregulated by IFNGR signaling blockade functions as a novel GVHD suppressor without compromising GVL in mice.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GVHD) and malignant relapse limit its therapeutic success. We previously demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction in GVHD while preserving graft-versus-leukemia (GVL) effects. However, the underlying molecular mechanisms remain inconclusive. In this study, we found that S100A9 is a novel GVHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1-/- and S100a9-overexpressing T cells significantly reduced GVHD without compromising GVL, altering donor T-cell trafficking to GVHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improved GVHD in our mouse model of xenogeneic human peripheral blood mononuclear cell transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab reduced human T-cell trafficking to the GVHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GVHD suppressor without compromising GVL.

A novel approach to operating room readiness for airborne precautions using simulation-based clinical systems testing.

BACKGROUND: The emergence of the COVID-19 disease as a global pandemic caused major challenges and strained busy operating room environments. This required institutions to rethink current system functioning and urgently develop safe medical practices and protocols. PURPOSE: To use a novel approach combining simulation-based clinical system testing with rapid cycle deliberate practice concepts for identifying latent safety threats presented by newly developed operating room COVID-19 protocols and collecting frontline staff recommendations for mitigation. METHODS: This study design combined a training/education approach with probing the systems function. The primary outcomes were the number of latent safety threats and staff evaluations of this approach for feasibility and utility on immediate and four-month post surveys. Participants started the simulation which took place in the operating room, in the assistant role before graduating to the primary airway manager. Simulation staff members observed the simulations and noted whether elements in the protocols/checklists were followed and whether latent safety threats were present using an observation form. Solutions to latent safety threats were sought during the debriefing period. RESULTS: This approach identified 17 latent safety threats not foreseen during the planning stages and allowed for corrections to the protocols prior to impacting patient outcomes. Post-simulation surveys indicated that the program was well received and all who responded agreed that it was worth the time it took. Fifty-seven percent of respondents to four-month follow-up survey reported using the work products to care for an actual COVID-19 patient. CONCLUSIONS: This study demonstrated a flexible methodology that effectively integrated simulation-based training and systems tests to train staff and detect latent safety threats in the new workflows and provide recommendations for mitigation. While COVID was the specific prompt, this approach can be applicable in diverse clinical settings for training medical staff, testing system function, and mitigating potential latent safety threats.

Simulation-Based System Analysis: Testing Preparedness for Extracorporeal Membrane Oxygenation Cannulation in Pediatric COVID-19 Patients.

INTRODUCTION: Coronavirus Disease-2019 presents risk to both patients and medical teams. Staff-intensive, complex procedures such as extracorporeal membrane oxygenation (ECMO) or extracorporeal cardiopulmonary resuscitation (eCPR) may increase chances of exposure and spread. This investigation aimed to rapidly deploy an in situ Simulation-based Clinical Systems Testing (SbCST) framework to identify Latent Safety Threats (LSTs) related to ECMO/eCPR initiation during a pandemic. METHODS: The adapted SbCST framework tested systems related to ECMO/eCPR initiation in the Neonatal and Pediatric Intensive Care Units. Systems were evaluated in six domains (Resources, Processes/Systems, Facilities, Clinical Performance, Infection Control, and Communication). We conducted three high-fidelity simulations with members from the Neonatal Intensive Care Unit General Surgery, Pediatric Intensive Care Unit Cardiovascular Surgery (CV), and Pediatric Intensive Care Unit General Surgery teams. Content experts evaluated systems issues during simulation, and LSTs were identified during debriefing. Data were analyzed for frequency of LSTs and trends in process gaps. RESULTS: Sixty-six LSTs were identified across three scenarios. Resource issues comprised the largest category (26%), followed by Process/System issues (24%), Infection Control issues (24%), Communication issues (17%), and Facility and Clinical Performance issues (5% each). LSTs informed new team strategies such as the use of a "door/PPE monitor" and "inside/outside" team configuration. CONCLUSIONS: The adapted SbCST framework identified multiple LSTs related to ECMO/eCPR cannulation and infection control guidelines in the setting of Coronavirus Disease-2019. Through SbCSTs, we developed guidelines to conserve PPE and develop optimal workflows to reduce patient/staff exposure in a high-risk procedure. This project may guide other hospitals to adapt SbCSTs strategies to test/adjust rapidly changing guidelines.

Extracorporeal Membrane Oxygenation as a Bridge to Chimeric Antigen Receptor T-cell Therapy for Severe Refractory Sepsis in the Setting of Relapsed Refractory Pediatric Acute Lymphoblastic Leukemia: A Case Report.

Pediatric oncology patients with sepsis are at higher risk of morbidity and mortality compared with pediatric patients without malignancy. Historically, patients with relapsed and/or refractory disease were not considered candidates for aggressive life support strategies including extracorporeal membrane oxygenation support. CASE SUMMARY: We report a 4-year-old female with relapsed refractory pre-B cell acute lymphoblastic leukemia preparing for chimeric antigen receptor T cell therapy with tisagenlecleucel who was admitted with fever and neutropenia. She progressed to refractory septic shock secondary to Escherichia coli bacteremia and required escalation of hemodynamic support to venoarterial extracorporeal membrane oxygenation cannulation. She cleared her E. coli bacteremia, was decannulated, subsequently received her chimeric antigen receptor T-cell therapy, and was declared disease free 1 month from her initial presentation. CONCLUSION: The ability to provide chimeric antigen receptor T-cell therapy at designated institutions can augment extracorporeal membrane oxygenation candidacy discussions in oncology patients with relapsed disease and may make extracorporeal membrane oxygenation candidacy for oncology patients with refractory sepsis more favorable.